STING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment

Steven Lohard, Nathalie Bourgeois, Laurent Maillet, Fabien Gautier, Aurélie Fétiveau, Hamza Lasla, Frédérique Nguyen, Céline Vuillier, Alison Dumont, Agnès Moreau-Aubry, Morgane Frapin, Laurent David, Delphine Loussouarn, Olivier Kerdraon, Mario Campone, Pascal Jézéquel, Philippe P. Juin () and Sophie Barillé-Nion ()
Additional contact information
Steven Lohard: CRCINA, INSERM, Université d’Angers, Université de Nantes
Nathalie Bourgeois: CRCINA, INSERM, Université d’Angers, Université de Nantes
Laurent Maillet: CRCINA, INSERM, Université d’Angers, Université de Nantes
Fabien Gautier: CRCINA, INSERM, Université d’Angers, Université de Nantes
Aurélie Fétiveau: CRCINA, INSERM, Université d’Angers, Université de Nantes
Hamza Lasla: SIRIC ILIAD, Nantes
Frédérique Nguyen: CRCINA, INSERM, Université d’Angers, Université de Nantes
Céline Vuillier: CRCINA, INSERM, Université d’Angers, Université de Nantes
Alison Dumont: CRCINA, INSERM, Université d’Angers, Université de Nantes
Agnès Moreau-Aubry: CRCINA, INSERM, Université d’Angers, Université de Nantes
Morgane Frapin: UMR 1280 PhAN, Université de Nantes, INRA
Laurent David: Nantes Université, CHU Nantes, Inserm, CRTI, UMR 1064, ITUN
Delphine Loussouarn: Service d’Anatomie Pathologique, CHU Nantes
Olivier Kerdraon: SIRIC ILIAD, Nantes
Mario Campone: CRCINA, INSERM, Université d’Angers, Université de Nantes
Pascal Jézéquel: CRCINA, INSERM, Université d’Angers, Université de Nantes
Philippe P. Juin: CRCINA, INSERM, Université d’Angers, Université de Nantes
Sophie Barillé-Nion: CRCINA, INSERM, Université d’Angers, Université de Nantes

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract A fascinating but uncharacterized action of antimitotic chemotherapy is to collectively prime cancer cells to apoptotic mitochondrial outer membrane permeabilization (MOMP), while impacting only on cycling cell subsets. Here, we show that a proapoptotic secretory phenotype is induced by activation of cGAS/STING in cancer cells that are hit by antimitotic treatment, accumulate micronuclei and maintain mitochondrial integrity despite intrinsic apoptotic pressure. Organotypic cultures of primary human breast tumors and patient-derived xenografts sensitive to paclitaxel exhibit gene expression signatures typical of type I IFN and TNFα exposure. These cytokines induced by cGAS/STING activation trigger NOXA expression in neighboring cells and render them acutely sensitive to BCL-xL inhibition. cGAS/STING-dependent apoptotic effects are required for paclitaxel response in vivo, and they are amplified by sequential, but not synchronous, administration of BH3 mimetics. Thus anti-mitotic agents propagate apoptotic priming across heterogeneously sensitive cancer cells through cytosolic DNA sensing pathway-dependent extracellular signals, exploitable by delayed MOMP targeting.

Date: 2020
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DOI: 10.1038/s41467-019-13689-y

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